Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics

Definitions

• the present invention relates to the discovery of the use of a pharmaceutical component in the treatment of disorders related to anxiety and depression.
• Anxiety in humans results in a feeling of worry, insecurity, physical or mental disorder or waiting for indeterminate danger.
• Two types of anxiety are also distinguished: state anxiety and trait anxiety.
• State anxiety is a "normal” anxiety related to a specific situation in which the subject is located.
• the trait anxiety is a "pathological" anxiety, constitutive of a subject. It is permanent and independent of a particular situation.
• Depression is defined by so-called depressive episodes in which the patient has a lowering of mood, a reduction of energy and a decrease in activity. During a depression, there is also an impairment of the ability to feel pleasure, a loss of interest and a rapid decrease in the ability to concentrate. There is also significant fatigue even after a minimal effort, sleep disorders ... Patients often feel a decrease in self-esteem, feelings of guilt and worthlessness that can go as far as a desire for death and the development of suicidal thoughts. Depending on the number and severity of symptoms, three degrees of depression severity are defined: mild, moderate, and severe depression.
• the subject has anxiety symptoms that are triggered exclusively or mainly by one or more specific situations and without danger. As a result, the patient will seek to avoid these situations or endure them with apprehension. This phobic anxiety is often associated with depression.
• the subject has both anxious symptoms and depressive symptoms with no clear predominance of one or the other and the intensity of one or the other justifies a separate diagnosis.
• OCD Obsessive Compulsive Disorder
• This disorder is characterized by obsessive ideas or recurring compulsive behaviors. Obsessive thoughts burst into the subject's consciousness in a repetitive and stereotypical way, even when the person tries to avoid them. Compulsive behaviors are also repetitive stereotyped activities for which the subject feels no direct pleasure but can not help but accomplish. They are intended to prevent the occurrence of an event, objectively unlikely, involving a misfortune for the subject. The latter generally recognizes the educaity of his behavior and makes repeated efforts to stop it. This disorder is almost always accompanied by anxiety and depression.
• Post-traumatic stress disorder develops as a result of the subject's (direct or indirect) exposure to a traumatic event in the context of death, death threats, serious injury or sexual assault ...
• a traumatic event in the context of death, death threats, serious injury or sexual assault ...
• this traumatic event represents a situation of extreme stress. It results in a set of specific symptoms and behaviors. For example: reviviscences (repetitive and invasive memories of the event, nightmares ...), avoidance behaviors (avoidance of memories, thoughts, people, situations ... recalling the traumatic event), cognitive and emotional alterations (tendency to blame, persistent negative emotions ...) and finally the hyperactivation of the nervous system (hypervigilance, difficulty of sleep ).
• Benzodiazepines whose leader is diazepam (Valium® ). These molecules initially presented as effective and of a relatively good tolerance have been and are still much prescribed, especially in France and the United States.
• Benzodiazepines have the ability to bind to a cellular receptor, normally reserved for GABA (g-aminobutyric acid). This natural chemical compound is the main inhibitor of the central nervous system. By binding to the cellular receptor, benzodiazepines increase the affinity of these receptors for GABA, and thus increase its power of action tenfold.
• GABA g-aminobutyric acid
• serotonin (5-hydroxytryptamine or 5-HT). It is a neurotransmitter released at the time of information exchange between a transmitting neuron and a receiving neuron.
• SSRIs are Selective Serotonin Reuptake Inhibitors, for example, fluoxetine (Prozac®) or vortioxetine (Trintellix®, Brintellix®).
• glutamate Another neurotransmitter, glutamate, is also the subject of intensive research to develop new drugs. It is now accepted that glutamate activates several types of receptors (EPHP memory of M. Teigell-Webb): glutamate acts on three ionotropic receptors, characterized and named by the name of their most selective agonist: N-receptors. methyl-D-aspartate (NMDA), kainate (KA), and ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA).
• NMDA methyl-D-aspartate
• KA kainate
• AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate
• the NMDA receptor study has developed more rapidly as research has shown that NMDA receptors are involved in interesting aspects of brain function.
• NMDA receptors play a wide variety of physiological roles: neuronal differentiation, formation of synaptic connections during development, synaptic plasticity in adults.
• the NMDA receptor is involved in learning and short-term memory; it participates in certain areas of the hippocampus to increase synaptic efficiency (or long-term potentiation) that would serve as a storage medium for information.
• the involvement of the NMDA receptor in the increase of anxious behavior following exposure to stress (RE Adamek et al, Physiology & Behavior, Vol 65, Nos 4/5, pp. 723-737, 1999) makes it a prime target for treatment development for PTSD.
• Noncompetitive NMDA receptor antagonists are molecules capable of binding to a regulatory site different from that of glutamate.
• NMDA receptor inhibiting peptides Patent EP2175873
• channel blockers are agents that bind within the channel associated with the NMDA receptor when the latter is in the "open” position (depolarized cell and bound glutamate).
• channel blockers are ketamine, memantine ... This last molecule has already showed neuroprotective effects. For example, it is already used for the treatment of Alzheimer's disease, but it has also been tested to treat behavioral disorders of children (autism), as for example in patent US2010081723A1.
• ketamine noncompetitive antagonists binding to the phencyclidine (PCP) site of the NMDA receptor
• PCP phencyclidine
• ketamine, dizocilpine, memantine have also been tested to relieve post-test state anxiety. traumatic (Arthur L. Womble, AANA Journal April 2013 Vol 81, No. 2.).
• ketamine and dizocilpine the positive results of these studies are strongly clouded by side effects (hallucinations, flashbacks, paranoia ). Note that ketamine strongly inhibits sensory filtering.
• ketamine is nevertheless continued by several teams who have shown an interesting prophylactic effect when the molecule is injected at one time, 1 week before conditioning to fear in rodents (C. Denny et al, in Neuropsychopharmacology (2017), 1 -13), resulting in a significant reduction in tetany, during the stabilization phase. Nevertheless, the effect is only visible at high doses for this model (30 mg / kg) and is not reproduced if the treatment is concomitant (or just precedes) the conditioning or if the protective treatment is done too early ( 1 month in advance).
• US 2014/057988 A1 also proposes the use of ketamine as an NMDA receptor antagonist for the inhibition, amelioration or treatment of mild anxiety development, with mild anxiety being defined in this document as a feeling of malaise or apprehension.
• mild anxiety being defined in this document as a feeling of malaise or apprehension.
• WO 2014/191424 describes the use of derivatives of memantine, especially 2-fluoroethyl normemantine, in the treatment of neurodegenerative diseases such as Alzheimer's or Parkinson's disease.
• Memantine has also been used to treat anxiety disorders, with or without depression such as PTSD and obsessive-compulsive disorder (G. Sani, CNS Drugs 2012; 26 (8): 663-690 ).
• the action of memantine is positive when used in combination (augmentation therapy) with other molecules. Its effectiveness is much lower and controversial when used as monotherapy.
• memantine has been associated with SSRIs such as fluoxetine or citalopram, or with other tricyclic antidepressants such as clomipramine.
• SSRIs such as fluoxetine or citalopram
• other tricyclic antidepressants such as clomipramine.
• memantine is well tolerated for low daily doses (less than about 15 mg / day).
• memantine seems to have hyper-tranquilizing effects not sought (drowsiness, fatigue, apathy %), and also lead to high doses increased dizziness (NR Swerdlow, Neuropsychopharma., 2009, 34, 1854-1864) as well as a rebound effect repeatedly reported by patients on internet forums.
• memantine especially in high doses, or the fact that it is not anxiolytic, is capable of inducing schizophrenia-like side effects.
• catecholaminergic agents Ducrocq, F., Encephalon, 2005; 31: 212-26. They have been implemented in pharmacological interventions aimed at directly eliminate noradrenergic hyperreactivity, and studied through open and double-blind trials on small numbers. These agents are in particular clonidine, guanfacine, prazozine and propranolol. Among these molecules, propranolol has been the subject of the most important work to date.
• the Applicant has therefore imagined using a molecule structurally derived from memantine but having a very different dipole moment generated by the introduction of a fluorine atom to treat the anxiety, associated or not with depression.
• the Applicant has surprisingly discovered that the molecule can act as well in protection, that is to say by a concomitant administration to the traumatic event, as for further treatment or delayed .
• the Applicant has further determined that the molecule does not exhibit the numerous unwanted side effects of state-of-the-art or proposed treatments under investigation.
• the compound (I) for its use according to the invention is characterized in that it lacks a schizophrenic induction effect.
• the compound (I) does not induce - at doses allowing the treatment or prevention of an anxiety disorder - schizophrenia or associated symptoms such as schizophrenic delusions, paranoid delusions, hallucinations, disturbances of attention, withdrawal, incoherence or disorganization.
• the invention provides a compound for its use according to the first embodiment, characterized in that the pharmaceutically acceptable salt corresponds to formula (II)
• X denotes a counter anion selected from the group consisting of chloride, bromide, iodide, acetate, methane sulphonate, benzene sulphonate, camphorsulphonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate and tosylate. It is also a third object of the invention to provide a compound for use according to one of embodiments 1 or 2, characterized in that the anxiety disorder is associated with depression.
• the compound is characterized in that it lacks a schizophrenic induction effect.
• the invention also aims in a fifth embodiment, a compound for use according to one of embodiments 1 to 4, characterized in that the anxiety disorder is selected from the group consisting of the post-stress state.
• traumatic PTSD
• specific phobia phobia
• social phobia phobia
• generalized anxiety disorder panic disorder with or without agoraphobia
• obsessive-compulsive disorder e.g., PTSD, specific phobia, social phobia, generalized anxiety disorder, panic disorder with or without agoraphobia and obsessive-compulsive disorder.
• the compound is characterized in that it lacks a schizophrenic induction effect.
• the invention also provides a compound for its use according to one of embodiments 1 to 5, characterized in that it is used for a treatment for preventing the appearance of related anxiety disorders. to post traumatic stress.
• the compound is characterized in that it lacks a schizophrenic induction effect.
• the treatment of anxiety disorders related to post-traumatic stress includes in particular the treatment of any combination of at least one of the DSM 5 criteria on the PTSD selected from the group consisting of: reviviscence, avoidance, cognition and negative mood and hyperreactivity.
• the compound (I) or (II) can be administered in the form of doses comprising 1 mg to 1000 mg of compound (I) or (II), for example 5 to 250 mg, by for example between 5 to 100 mg and preferably from 5 to 30 mg of compound (I) or (II).
• the doses in question may be administered, for example, 1 to 4 times a day, for example once, for example 2 times, in particular 3 times or even 4 times.
• the compound (I) for use according to the invention is characterized in that it lacks a schizophrenic induction effect.
• the invention provides a compound for use according to Embodiment 6, characterized in that the treatment comprises administering the compound concomitantly to the traumatic event causing the post-traumatic stress.
• An eighth embodiment of the invention also provides a compound for its use according to Embodiment 6, characterized in that the treatment comprises administering the compound for 4 to 18 weeks following the traumatic event causing the post-stress. traumatic.
• the compound may be administered for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 weeks.
• the compound is characterized in that it lacks a schizophrenic induction effect.
• the invention is directed to a compound for use according to embodiment 9, characterized in that the patient having an anxiety disorder is following an antidepressant therapy selected from behavioral therapies and pharmacological antidepressant treatments.
• antidepressant pharmacological treatment it is understood the administration of at least one chemical molecule known for the treatment of depression.
• serotonin reuptake inhibitors such as fluoxetine, vortioxetine, fluvoxetine, sertraline, paroxetine, citalopram, escitalopram, duloxetine, milnacipram, venlafaxine, indalpine. , zimelidine, dapoxetine.
• the invention is directed to a compound for use according to Embodiment 10, characterized in that the patient is on a propanolol-based treatment.
• the invention relates to a compound for use according to one of embodiments 1 to 1 1, characterized in that the anxiety disorder is accompanied by acute seizures and episodes of anxiety.
• the invention is also directed, in a thirteenth embodiment, to a combination product, in particular for a simultaneous, separate or spread over time use, comprising the following components: a component (A) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient
• a component (B) comprising propranolol and at least one pharmaceutically acceptable excipient.
• the product according to the invention is characterized in that it lacks a schizophrenic induction effect.
• a fourteenth embodiment of the invention to provide a combination product comprising the following components: a component (A) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof
• a component (C) comprising an antidepressant, in particular one of the serotonin reuptake inhibitors described in Embodiment 10; wherein each of the components (A) and (C) is formulated with at least one pharmaceutically acceptable excipient.
• the product according to the invention is characterized in that it lacks a schizophrenic induction effect.
• the invention also provides a product according to embodiment 13, further comprising in combination, a component (D) comprising ketamine formulated with a pharmaceutically acceptable excipient.
• the invention also provides a product according to embodiment 14, further comprising in combination, a component (D) comprising ketamine formulated with a pharmaceutically acceptable excipient.
• the invention also provides a product according to embodiment 13, wherein components (A) and (B) are suitable for simultaneous, separate or time-spread administration.
• the invention is directed to a product according to embodiment 14, wherein components (A) and (C) are suitable for simultaneous, separate or time-spread administration.
• the invention is directed to a product according to embodiment 15, wherein components (A), (B) and (D) are suitable for simultaneous, separate or time-spread administration. .
• the invention is directed to a product according to embodiment 16, wherein components (A), (C) and (D) are suitable for simultaneous, separate or time-spread administration.
• the invention relates to a product according to one of the embodiments 13 to 20, for its use in the prevention or treatment of an anxiety disorder in a patient.
• the invention relates to a product for its use according to embodiment 21, characterized in that the patient follows cognitive behavioral therapy.
• the invention also provides a product for its use according to embodiment 22, characterized in that the treatment of the anxiety disorder is subsequent to behavioral cognitive therapy.
• the invention is directed to a product according to one of the embodiments 13 or 17, for its use in the prevention or treatment of an anxiety disorder in a patient, said patient having undergone repeated abuse, especially during childhood.
• the invention provides a product for its use according to embodiment 24, characterized in that said patient follows cognitive behavioral therapy.
• the invention also relates to a product for its use according to embodiment 25, characterized in that the components (A) and (B) are used separately in time and after cognitive behavioral therapy.
• FENM 2-fluoroethylnormemantine
• the molecule (I) may be in equilibrium with a protonated form of formula (II), in which X denotes a counterion originating from the biological medium or chosen from chloride, bromide, iodide, acetate, methane sulphonate, benzene sulphonate, camphorsulphonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate, tosylate.
• the product of formula (II) is therefore a pharmaceutically acceptable salt of the product of formula (I).
• FENM-HCl a particularly preferred pharmaceutically acceptable salt of fluoroethylnormemantine whose counterion is a chloride ion, ie FENM-HCl.
• the applicant has demonstrated that the compound (I) (or a salt thereof, particularly FENM-HCl) can be used for the treatment of anxiety, associated or not with depression.
• the Applicant has surprisingly discovered that the compound (I) or an acceptable pharmaceutical salt thereof can act as well in protection, that is to say by concomitant administration to traumatic event, only during further or delayed treatment.
• the Applicant has furthermore determined that the molecule does not exhibit the numerous undesirable side effects of the treatments of the state of the art or proposed during the investigation.
• the applicant has also demonstrated an anxiolytic activity of the product (I) described here (light dark box test and light gradient). On the contrary, it has been demonstrated under the same conditions that Memantine has no anolyolytic activity.
• the product (I) described here has a very significant anxiolytic activity, and its affinity with the NMDA receptor (measured in Ki) is of the same order of magnitude as that of memantine.
• the term "concomitant administration to the traumatic event” is understood to mean that the compound (I) is administered in a window of time ranging from 48 hours before the traumatic event to 72 hours after the traumatic event. traumatic event.
• This "concomitant administration to the traumatic event” may also be between 48 hours before and 48 hours after the traumatic event, or 48 hours before and 24 hours after the traumatic event, or 24 hours before and 24 hours after the traumatic event.
• concomitant administration may be prolonged for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 weeks to result in increased protection. efficient.
• the object of the present invention is therefore first of all to provide a method for treating patients suffering from anxiety disorders, whether or not associated with depression, by administering in particular a compound of formula (I) or a pharmaceutically acceptable salt of formula (II) ).
• the method does not induce a schizophrenic induction effect.
• the present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt of formula (II), in the manufacture of a medicament for the treatment of anxiety disorders, associated or not with a depression.
• anxiolytic and possibly antidepressant activity of the compounds of formula (I) can be evaluated using appropriate animal paradigms.
• the Applicant has discovered that the compounds of formula (I) or (II) according to the present invention have significant anxiolytic properties and this from the first injection for a dosage of 10 mg / kg, unlike the memantine which induces an increased presence time in the dark compartment.
• a molecule such as fluoxetine has such anxiolytic activity for doses of 5mg / kg but only after 7 days of treatment.
• the compound according to the invention significantly limits the avoidance of the most enlightened zone of the field by the rodent during the exposure phase, or cancels it completely, in particular at a dose of 10 mg / kg.
• the Applicant has discovered that the compound according to the present invention induces a significant decrease in the immobility time in the rats as when they are treated with the memantine or the ketamine, which translates antidepressant behavior of these molecules and compounds.
• the Applicant has also confirmed this surprising interest of a compound according to the invention in the treatment of anxiety disorders, associated or not with depression by using them in a fear conditioning test with extinction phase and stabilization.
• This paradigm commonly used to test the efficacy of the treatments of PTSD has shown that a compound according to the present invention, surprisingly, allows, especially at doses of 10mg / kg and 20mg / kg to protect the patient against the persistence of disorders during the stabilization phase, and more particularly when the compound is administered concomitantly with the conditioning phase.
• no effect is observed or for propranolol.
• the effects observed for MENM are equivalent to or greater than those observed by C. Denny for ketamine injected in a much higher amount, one week before conditioning.
• the Applicant has found that a similar beneficial effect in intensity, and more particularly for the same doses, could be observed when the compound according to the invention was administered before the stabilization phase, that is during a syndrome. of consolidated PTSD. In the same test, no effect is observed or for propranolol.
• the compounds according to the invention are, finally, also effective for the elimination of persistent disorders, in particular when they are administered during the extinction phase, more particularly at a dose of 20 mg / kg.
• propranolol decreases tetany during the extinction phase, but this beneficial effect is lost during the stabilization phase.
• a significant rebound effect is observed during the stabilization phase for memantine when it is administered during the extinction phase. This effect, in addition to demonstrating different mechanisms of action for memantine and FENM, is consistent with the clinically observed inefficacy of memantine for the treatment of PTSD.
• the compound according to the invention can be administered in various ways in order to obtain anxiolytic or antidepressant effects.
• the compound according to the invention may be administered alone or in the form of pharmaceutical preparations, to the patient to be treated, orally or parenterally (subcutaneously or intravenously ).
• the amount of the administered compound may vary and may be any amount responsible for anxiolytic and / or antidepressant effects. Depending on the patient and the mode of administration, the amount of compound administered may vary within a wide range from 0.01 mg / kg to 20 mg / kg, preferably from 0.05 mg / kg to 15 mg / kg of patient weight. per dose.
• the unit doses of compound according to the invention may contain, for example, from 5 mg to 1000 mg, preferably from 5 to 30 mg, and may be administered for example from 1 to 4 times per day.
• the subject of the present invention is the use of a medicament formulated from the compound according to the invention in combination with a therapeutic pharmaceutical or cognitive behavioral method for the treatment of anxiety disorders, whether or not associated with depression.
• cognitive behavioral psychotherapies or cognitive therapies.
• behavioral, CBT grouping a set of treatments for psychiatric disorders (including addictions, psychoses, depressions and anxiety disorders) who share an approach according to which therapy is based on knowledge from scientific psychology. It obeys relatively standardized protocols. She often evaluates the patient's progress during therapy. She accepts the medicine approach based on the facts. CBTs have the particularity of tackling the patient's difficulties in the "here and now” by practical exercises centered on the symptoms observable through the behavior and by the accompaniment by the therapist who aims to intervene on the mental processes also cognitive processes, conscious or not, considered as the origin of emotions and their disorders.
• the standardization of CBT practice has contributed to the recognition of their effectiveness by their reproducibility which is one of the requirements of the scientific approach. They are particularly indicated for anxiety disorders (especially phobias) and addictions.
• the applicant proposes to implement a combination of the prophylactic administration of ketamine and a drug containing a compound according to the invention after traumatic exposure, in order to treat PTSD.
• the Applicant proposes to use a combination of the administration of propranolol associated with cognitive therapy during an initial treatment period of PTSD and a treatment with a drug containing the compound according to the invention during the withdrawal phase, to treat the anxiety disorders present in patients who have been abused, especially during childhood.
• the open field test This consists of the forced exposure of the animal (rat or mouse) to a new environment and the observation of its behavior.
• the animal is usually placed in a cage or box whose floor is squared and he does not know. Locomotor activity and behavior are then evaluated by recording the number of crossings in the gridlines, the frequency of the setbacks, the number of entries, and the time spent in the central squares.
• This animal model is considered a good model of "normal" anxiety when adapting to a new environment. It has a good predictability of the human response to treatments (L. Prut, European Journal of Pharmacology 463 (2003) 3-33).
• the open space test is also useful, when extended (2 hour behavior recording time), because it tracks the activity animals and therefore their waking state, while short time measurements give information on anxiety.
• the open-space test with light gradient the two models described above can be judiciously coupled to verify the anxiolytic potential of a molecule, eliminating the "burrowing" effect induced by the presence of the dark compartment.
• This test has been used for many years with rats or mice, to test the activity of antidepressants (F. Borsini, Psychopharmacology (1988) 94: 147-160). It consists of placing the animal in a jar filled with water at room temperature. After 15 minutes (pre-test session), the animal is taken out of the water and dried. Twenty-four hours later, the animal is again exposed to the above conditions and the total immobility period for a period of 5 minutes is recorded (test session). The animal is judged immobile when it only makes the movements necessary to keep the head out of the water. This immobility is easier to evaluate in rats than in mice with less explicit movements.
• This animal model consists of Pavlovian-type fear conditioning (Zovkic, Neuropsychopharmacology Reviews (2013) 38, 77-93): mice (or rats) are trained to associate exposure to danger (electric shock ...) the presence of an index or a specific environment (sound index for example). The memory of this association (danger-index) is tested later by measuring tetany behavior (by fear) when the animal is re-exposed to the conditioning index in the absence of real danger.
• Fear conditioning has many benefits as a model of PTSD.
• rodents like patients with PTSD, are subjected to a traumatic event and the memory of this event persists for long periods of time.
• the reviviscences of the traumatic event or the typical avoidances of the PTSD can be modeled by the exposure of the rodent to the sound index or the context associated with the danger, without that it requires a real re-exposure to the traumatic event itself (electric shock).
• the hyperactivity of the nervous system observed in patients with PTSD can be evaluated by comparing the amplitude and appearance of the bursts produced in response to a sound reminding them of the trauma.
• PTSD studies have shown that the areas of the brain involved include the amygdala, hippocampus, and prefrontal cortex that are also involved in fear conditioning of animals.
• PTSD symptoms are evaluated after a certain delay, without exposure to danger, to simulate the long-term appearance of the pathology of PTSD.
• this phase is placed 24 hours after the conditioning phase.
• the conditioned animal is driven so that the conditioning index (the sound) no longer predicts the occurrence of the danger (the electric shock).
• extinction may appear as the cancellation of learning in the preceding fear, it is not equivalent to an erasure of memory or to a definitive oblivion, since, on the one hand, tetany is not not completely eliminated by the extinction phase and, on the other hand, that the response to the stimulus can reappear spontaneously or following a shock.
• the extinction protocols model the learning the normal response (not motivated by fear) to the (sound) index and are very useful in modeling PTSD.
• a stabilization phase spaced 24 hours apart. Typically, this phase places, again, the animals under the conditions of the extinction phase. It then makes it possible to detect shifted performances of treatments, but also resurgences of tetany (rebound effect).
• the pre-impulse inhibition test is based on the brain's ability to adapt to a moderate intensity stimulus so as to limit the effect of this same high intensity stimulus.
• the animals are placed in a soundproof cage and subjected to either a sound pulse of 120 decibels (dB) or a sequence of 2 pulses spaced a hundred milliseconds apart, the second pulse being of fixed intensity 120 dB and the first variable intensity between 70 and 85 dB).
• the first sound pulse has the ability to partially inhibit the burst caused by the sound of maximum intensity. In animals with psychotic disorders of a schizophrenic nature, this inhibition is more or less eliminated.
• the PPI test in rodents is a powerful test in that it is reproducible in humans in which it can detect schizophrenic disorders, as well as the adverse effect of pharmaceutical treatments (PCP, benzodiazepine, ketamine).
• FENM fluoroethylnormemantine
• the tested substances are administered to the rats intraperitoneally in a volume of 5 ml / kg, 30 minutes before performing the behavioral tests.
• the injected solutions contain one or the other of the molecules in the form of one of their salt, a hydrochloride (memantine, HCl and FENM.HCl) for the nitrogenous derivatives and as such for propranolol, at the concentrations indicated in FIG. below in a 95% mixture (NaCl 0.9% ww in water) / 5% Ethanol. In each experiment, the dose per kilogram is referenced.
• a hydrochloride memantine, HCl and FENM.HCl
• the animals are given a constant volume of solution (with differences of weight) equal to 5 ml / kg or 1 .5 ml for a rat of 300 g.
• the control solution is a saltwater solution.
• the locomotor activity of the animals, and the "normal" anxiety related to the discovery of an unknown environment, are measured in an open field using a 2-hour video tracking system. 30 minutes after injection solutions to test.
• the recorded data includes, among other things, a reading every 5 minutes, the time spent in the central squares, the vertical activity, and the number of displacements.
• Example 2 Treatment of anxiety (paradigm of the lighted-dark box)
• the test of the lighted-dark box was used. Since it is based on the innate aversion of rodents for light, the increase in time spent in the illuminated compartment is therefore considered to reflect a lower level of anxiety.
• the box used for this test is divided into a high-power white light behavior (600 lux) and a black behavior with a lid (about 5 lux).
• the number of entries and the time spent in the illuminated compartment (anxiety zone) are recorded for 10 minutes by a video tracking system.
• the system also makes it possible to differentiate the periods between 0 and 5 minutes and between 5 and 10 minutes.
• Table 4 shows the times of presence in the illuminated compartment for different doses of FENM.HCl, in comparison with memantine and a control saline solution.
• results show a significant and significant increase (Student t-test p ⁇ 0.01) of the time spent in the illuminated compartment of the box for animals treated with FENM solution 10 mg / kg, compared to control, whereas no effect is observed for memantine.
• This result demonstrates the anxiolytic effect of the compound according to the invention and also a mode of action and a different effect compared to the memantine. This demonstrates that memantine has no anxiolytic effect.
• Example 3 treatment of anxiety (paradigm of the field illuminated by a light gradient)
• test of the light-dark box has been modified, by eliminating compartmentalization of the box and using a high intensity light gradient.
• the animals are exposed to a 12-minute sequence, broken down into three parts, 4 minutes in the dark (5 lux ambient light), 4 minutes in the presence of the light gradient and 4 minutes again in the dark. Displacements are recorded in the same way as for the open field test.
• the field of view is divided into 4 zones numbered from 1 to 4 depending on the increasing distance from the light source. Table 5 below shows the effects of different doses of FENM. HCl, compared to the control solution.
• Example 4 treatment of depression (forced swimming)
• the rats (12 per group) were forced to swim in a tank filled with water at 23 ° C (10 minutes on the first day to allow habituation in the middle and 6 minutes on the second day ).
• the behavior of the rats (stop swimming, decrease in activity) is quantified by a video tracking system.
• the therapeutic solutions to be tested are administered on the second day 30 minutes before the experiment.
• the so-called resigned animals are those who will present a) a longer period of immobility and b) spend less time trying energetically (concentrically) out of the beaker, so behaving like "depressive".
• Table 6 below reports the effects observed on these two parameters in the presence of different doses of FENM. HCl, in comparison with memantine and a saline control solution.
• Example 5 treatment of PTSD (conditioning with fear + extinction + stabilization)
• the extinction protocols modeling the re-learning of the normal response (not motivated by fear) to the (sound) index are very useful in modeling of PTSD.
• the Applicant has used a fear conditioning test in which the index (conditional neutral stimulus) is a sound, coupled with a hazard (aversive unconditional stimulus) which is an electrical shock delivered by the floor of the box. This conditioning is followed by a phase of extinction of the fear with injection of the treatment solutions to be tested then by a test phase itself.
• FC Fear conditioning
• Context A white box in Table 7
• rats (8 per group) are subjected to 3 couples "son- electroshock "at times of 180s, 381s and 582s after placement in the box.
• Each sound lasts 20 s and each electroshock lasts 1 s with an intensity of 1 mA.
• the extinction phase of fear Is as follows: the rats are placed in a box similar to that which will be used for the final test (context B, pink box in Table 7), during a 25-minute session. During this session, there are 24 presentations of the same sound used during the conditioning session (duration of 20s each, separated by 35 s). Of course, no electric shock is delivered, we record the percentage of tetany time ("freezing") during the phase.
• Stabilization phase the day after the extinction phase, 30 minutes before the test phase, the rats receive an injection of salt water, then test their response to fear in context B by subjecting them to a sequence of 3 sounds (same sequence as used for conditioning), recording the percentage of time of immobility during this test phase.
• Table 8 reports the effects observed on the percentage of time immobile by the animals, during the stabilization phase, for different doses of FENM.HCl, in comparison with propranolol and a control saline solution, in three treatment conditions:
• the pre-impulse inhibition test is based on the brain's ability to adapt to a moderate intensity stimulus so as to limit the effect of this same high intensity stimulus.
• the animals (12 per group) are placed in a soundproof cage and subjected either to a sound pulse of 120 decibel (dB), or to a sequence of 2 pulses spaced a hundred milliseconds apart, the second pulse being of fixed intensity of 120 dB and the first variable intensity between 70 and 85 dB).
• the first sound pulse has the ability to partially inhibit the burst caused by the sound of maximum intensity. In animals with psychotic disorders of a schizophrenic nature, this inhibition is more or less eliminated.
• Table 9 reports the effects observed on these two parameters in the presence of different doses of FENM. HCl, in comparison with the memantine or with a saline control solution.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (6)

Applications Claiming Priority (2)

Publications (1)

Family

ID=62091972

Family Applications (1)

Country Status (8)

Cited By (3)

Citations (8)

• 2017
  • 2017-12-15 FR FR1762290A patent/FR3075038B1/fr active Active
• 2018
  • 2018-12-17 JP JP2020552138A patent/JP7301871B2/ja active Active
  • 2018-12-17 WO PCT/EP2018/085333 patent/WO2019115833A1/fr unknown
  • 2018-12-17 ES ES18815771T patent/ES2963655T3/es active Active
  • 2018-12-17 US US16/772,582 patent/US11464751B2/en active Active
  • 2018-12-17 CA CA3085585A patent/CA3085585A1/fr active Pending
  • 2018-12-17 CN CN201880089497.5A patent/CN111886005B/zh active Active
  • 2018-12-17 EP EP18815771.3A patent/EP3723742B1/fr active Active

Patent Citations (8)

Non-Patent Citations (15)

Also Published As

Similar Documents

Legal Events